Highly active antiretroviral therapy (HAART) does not eradicate HIV-1 infection from the body because reservoirs of cells harboring replication- competent virus persist in blood and lymphoid tissue even after years of treatment. Thus, there is a need to develop new therapeutic approaches targeting the pool of latently infected HIV-1-infected cells. We propose to facilitate evaluation of these new treatments by developing a new chimeric mouse model populated with HIV-1-infectious mouse cells as well as human T cells susceptible to HIV-1 infection. We have developed mice transgenic for a full-length proviral clone of R5-tropic HIV-1JR-CSF (JR-CSF mice) that displays plasma viremia and whose T cells, monocytes and dendritic cells produce infectious HIV-1. Cells from these mice have been tagged by crossing them with ROSA26 mice to yield mice transgenic for both the expression of HIV-1JR-CSF and beta-galactosidase. These mice have also been crossed with DO11.10 OVA (323-339)-TCR transgenic mice permitting generation of antigen-- specific memory CD4+ T cells containing replication-competent HIV-1. We now demonstrate that JR-CSF mouse cells transferred into thy/liv- SCID-hu mice function as a reservoir of HIV-1-infected cells capable of infecting the human T cells and human thymic implant. This is prevented as long as the mice were treated with HAART, but occurs after HAART is stopped, even after 1 month of HAART. Complete clearance of the JR-CSF cells capable of producing infectious HIV-1 would prevent infection of the hu-thy/liv implant after HAART was stopped. Thus, we could evaluate the efficacy of therapeutic interventions to target persistent HIV-1 reservoirs by transferring JR-CSF mouse cells into thy/liv-SCID-hu mice on HAART, treating the mice with the therapeutic candidates, stopping HAART treatment of the mice, and then evaluating the temporal onset of HIV-1 infection in the hu-thy/liv implant. We will establish the validity of the model system and use it to evaluate the efficacy of various treatments such as Env-directed toxins, and HIV- specific CTL to deplete the population of HIV-1-infected cells. We will also examine the efficacy of Env-directed toxin-treatment to eliminate reservoirs of HIV-1-infected cells using our well-established thy/liv- SCID-hu mouse system.